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Possible indomethacin-aminoglycoside interaction in preterm infants
Volume 107 Number 6
Editorial correspondence
991
the pattern of occurrence in this family is consistent with autosomal recessive inheritance. However, there may be more than one cause of CCM, or more than one disorder with significant overlap.
Michael S. Trautman, M.D. Susan L: Schelley, M.P.H. David K: Stevensott, M.D. Department of Pediatrics, Stanford University School of Medicine Stanjord, CA 94305 REFERENCES 1. 2.
Figure. Multiple bilateral asymmetric posterior rib gaps and short ventrolateral segments of ribs with costochrondraI junctions at lateral margins of thoracic cage.
Chest roentgenographic findings (Figure) were consistent with CMM syndrome. Serial neurologic examinations, EEGs, cranial ultrasound, and computed tomography scan were normal. An initial brainstem auditory evoked response was suggestive of bilateral conductive hearing loss and possible neurologic involvement on the right, but was considered inconclusive. Several attempts to wean the infant from the ventilator failed because of severe hypercarbia, and pulmonary function deteriorated further postnatally. Because of the worsening pulmonary function and refractory air hunger despite ventilatory assistance, mechanical ventilation was discontinued and the infant ws allowed to die. The inheritance pattern of CCM syndrome is not well understood. Both autosomal dominant and.recessive transmissions have been postulated. Although the deficiencies in the posterio r portion of affected ribs are the sine qua non for diagnosis, there is no clear-cut definition of the essential criteria for establishing the diagnosis. McNicholl et al 2 postulated autosomal recessive inheritance., Leroy, et aP reported a family in which the mother and two offspring had cleft palate, micrognathia, and rib anomalies; they suggested that the defects were consistent with autosomal dominant transmission of CCM syndrome. However, the typical rib defects were documented in only one sibling, and the rib defects in the mother were not the pathognomonic rib gap anomaly of the CCM syndrome. Other authors have reported isolated cleft palate in first-degree relatives of individuals with CCM syndrome, questioning the presence of variable expression of a dominant gene for this syndrome. In the present family, the phenotype of the two affected siblings is very characteristic for what has been described as CCM syndrome, with the possible exception of obvious congenital cerebral defects in either infant. (The requirement for cerebral anomalies in the diagnosis of CCM syndrome is dubious; the associated mental impairment might relate more to acquired central nervous system injury caused by birth injury or respiratory difficulties.) We found no evidence of consanguinity. The karyotypes of both affected infants were normal. Although we previously speculated about the existence of some teratogenic agent(s), ~
3.
Silverman FN, Strefling AM, Stevenson DK. Cerebrocosto-mandibular syndrome. J PEDtATR 1980;97:406. M~zNicholl G, Egan-Mitchell B, Murray JP. Cerebro-costomandibular synd?ome: a new familial developmental disorder. Arch Dis Child 1970;45:421. Leroy JG, Devos E A , Vanden Bulcke L J, Robbe NS. Cerebro:costo-mandibu!ar syndrome with autosomal dominant inheritance. J PEDIATR 1981;99:441.
Possible indomethacin-aminoglycoside interaction in preterm infants To the Editor The.development of transient oliguria and renal failure during indomethacin treatment Of patent ductus arteriosus in neonates is common, and the possible interaction with other potentia!ly nephrotoxic drugs, such as the aminoglycosides, is a cause for concern.
Zarfin et al. l present convincing evidence that the coadministration of indomethacin and amin0glycosides produces potentially dangerou s levels of the antibiotic in newborn infants. As the authors state, aminoglycoside accumulation can be expla!ned by the reduction in glomerular filtration rate (GFR) caused by indomethacin. It is generally believed that this drop in GFR is not peculiar to indomethaein but results from the inhibiiion of renal prostaglandin production and can be seen with other drugs that share the same pharmac01ogic action. To better elucidate the interaction between aminoglycosides and prostaglandin inhibit0rs, we carried o.ut an animal study to investigate the renal effects of concurrent gentamicin and acetylsalicylic acid (ASA) administration? Groups of rats received either gentamicin 80 mg/kg/day, ASA 200 mg/kg/day, both drugs, or saline solution (control) for 5 to 10 days. A S A was chosen instead of indomethacin because of its greater systemic tolerability by rats and longer inhibiting effect on renal prostaglandin production. Our data indicate that prostaglafidin inhibition actually worsens aminoglycoside-induced renal failure, perhaps by blunting the specific PGE2 increase induced by gentamicin. Renal gentamicin concentrations were lowered by coadministration of ASA, despite increased toxicity. This could be a specific effect of ASA. Alternatively, the obset:ved decrease in GFR could account for the decreased renal concentrations in the gentamicin + ASA group. Humans with chronic renal failure display lower renal uptake and
992
Editorial correspondence
The Journal of Pediazrt'es December 1985
higher plasma levels of aminoglycosides? We did not monitor plasma levels, but it is conceivable that they were more elevated in the rats undergoing more severe renal failure (gentamicin + ASA group). Our findings support the concerns expressed by Zarfin et al. regarding a possible interaction between indomethacin and aminoglycosides. High plasma concentrations of aminoglycosides, whether they are the effect or the cause of decreased GFR, also can prove toxic to the inner ear?
Luigi Gagliardi, M.D. Divisione di Pediatria Ospedale di Lecco Via Ghislanzoni 22053 Lecco (CO), Italy
REFERENCES
1.
Zarfin Y, Koren G, Maresky D, et al. Possible indometha. cin-aminoglycoside interaction in preterm infants. J PED~A~a 1985;106:511. 2. Assael BM, Chiabrando C, Gagliard~L, et al. Prostaglan: dins and aminoglycoside nephrotoxicity. Toxicol Appl Pharmacol (in press)~ 3. Bennett WM, Hartnett MN, Craven R, et al. Gentamicin concentrations in blood, urine, and renal tissue of patients with end-stage renal disease. J Lab Clin Med 1977;90:389. 4. Assael BM, Parini R, Rusconi F. Ototoxicity ofaminoglyeoside antibiotics in infants and children. In: Nelson JD, McCracken GH, eds. Clinical reviews in pediatric infectious disease. Philadelphia: BC Decker, 1985:107.
Editorial correspondence
991
the pattern of occurrence in this family is consistent with autosomal recessive inheritance. However, there may be more than one cause of CCM, or more than one disorder with significant overlap.
Michael S. Trautman, M.D. Susan L: Schelley, M.P.H. David K: Stevensott, M.D. Department of Pediatrics, Stanford University School of Medicine Stanjord, CA 94305 REFERENCES 1. 2.
Figure. Multiple bilateral asymmetric posterior rib gaps and short ventrolateral segments of ribs with costochrondraI junctions at lateral margins of thoracic cage.
Chest roentgenographic findings (Figure) were consistent with CMM syndrome. Serial neurologic examinations, EEGs, cranial ultrasound, and computed tomography scan were normal. An initial brainstem auditory evoked response was suggestive of bilateral conductive hearing loss and possible neurologic involvement on the right, but was considered inconclusive. Several attempts to wean the infant from the ventilator failed because of severe hypercarbia, and pulmonary function deteriorated further postnatally. Because of the worsening pulmonary function and refractory air hunger despite ventilatory assistance, mechanical ventilation was discontinued and the infant ws allowed to die. The inheritance pattern of CCM syndrome is not well understood. Both autosomal dominant and.recessive transmissions have been postulated. Although the deficiencies in the posterio r portion of affected ribs are the sine qua non for diagnosis, there is no clear-cut definition of the essential criteria for establishing the diagnosis. McNicholl et al 2 postulated autosomal recessive inheritance., Leroy, et aP reported a family in which the mother and two offspring had cleft palate, micrognathia, and rib anomalies; they suggested that the defects were consistent with autosomal dominant transmission of CCM syndrome. However, the typical rib defects were documented in only one sibling, and the rib defects in the mother were not the pathognomonic rib gap anomaly of the CCM syndrome. Other authors have reported isolated cleft palate in first-degree relatives of individuals with CCM syndrome, questioning the presence of variable expression of a dominant gene for this syndrome. In the present family, the phenotype of the two affected siblings is very characteristic for what has been described as CCM syndrome, with the possible exception of obvious congenital cerebral defects in either infant. (The requirement for cerebral anomalies in the diagnosis of CCM syndrome is dubious; the associated mental impairment might relate more to acquired central nervous system injury caused by birth injury or respiratory difficulties.) We found no evidence of consanguinity. The karyotypes of both affected infants were normal. Although we previously speculated about the existence of some teratogenic agent(s), ~
3.
Silverman FN, Strefling AM, Stevenson DK. Cerebrocosto-mandibular syndrome. J PEDtATR 1980;97:406. M~zNicholl G, Egan-Mitchell B, Murray JP. Cerebro-costomandibular synd?ome: a new familial developmental disorder. Arch Dis Child 1970;45:421. Leroy JG, Devos E A , Vanden Bulcke L J, Robbe NS. Cerebro:costo-mandibu!ar syndrome with autosomal dominant inheritance. J PEDIATR 1981;99:441.
Possible indomethacin-aminoglycoside interaction in preterm infants To the Editor The.development of transient oliguria and renal failure during indomethacin treatment Of patent ductus arteriosus in neonates is common, and the possible interaction with other potentia!ly nephrotoxic drugs, such as the aminoglycosides, is a cause for concern.
Zarfin et al. l present convincing evidence that the coadministration of indomethacin and amin0glycosides produces potentially dangerou s levels of the antibiotic in newborn infants. As the authors state, aminoglycoside accumulation can be expla!ned by the reduction in glomerular filtration rate (GFR) caused by indomethacin. It is generally believed that this drop in GFR is not peculiar to indomethaein but results from the inhibiiion of renal prostaglandin production and can be seen with other drugs that share the same pharmac01ogic action. To better elucidate the interaction between aminoglycosides and prostaglandin inhibit0rs, we carried o.ut an animal study to investigate the renal effects of concurrent gentamicin and acetylsalicylic acid (ASA) administration? Groups of rats received either gentamicin 80 mg/kg/day, ASA 200 mg/kg/day, both drugs, or saline solution (control) for 5 to 10 days. A S A was chosen instead of indomethacin because of its greater systemic tolerability by rats and longer inhibiting effect on renal prostaglandin production. Our data indicate that prostaglafidin inhibition actually worsens aminoglycoside-induced renal failure, perhaps by blunting the specific PGE2 increase induced by gentamicin. Renal gentamicin concentrations were lowered by coadministration of ASA, despite increased toxicity. This could be a specific effect of ASA. Alternatively, the obset:ved decrease in GFR could account for the decreased renal concentrations in the gentamicin + ASA group. Humans with chronic renal failure display lower renal uptake and
992
Editorial correspondence
The Journal of Pediazrt'es December 1985
higher plasma levels of aminoglycosides? We did not monitor plasma levels, but it is conceivable that they were more elevated in the rats undergoing more severe renal failure (gentamicin + ASA group). Our findings support the concerns expressed by Zarfin et al. regarding a possible interaction between indomethacin and aminoglycosides. High plasma concentrations of aminoglycosides, whether they are the effect or the cause of decreased GFR, also can prove toxic to the inner ear?
Luigi Gagliardi, M.D. Divisione di Pediatria Ospedale di Lecco Via Ghislanzoni 22053 Lecco (CO), Italy
REFERENCES
1.
Zarfin Y, Koren G, Maresky D, et al. Possible indometha. cin-aminoglycoside interaction in preterm infants. J PED~A~a 1985;106:511. 2. Assael BM, Chiabrando C, Gagliard~L, et al. Prostaglan: dins and aminoglycoside nephrotoxicity. Toxicol Appl Pharmacol (in press)~ 3. Bennett WM, Hartnett MN, Craven R, et al. Gentamicin concentrations in blood, urine, and renal tissue of patients with end-stage renal disease. J Lab Clin Med 1977;90:389. 4. Assael BM, Parini R, Rusconi F. Ototoxicity ofaminoglyeoside antibiotics in infants and children. In: Nelson JD, McCracken GH, eds. Clinical reviews in pediatric infectious disease. Philadelphia: BC Decker, 1985:107.